Superoxide and other reactive oxygen species play a pivotal role in a variety of vascular diseases. This[unreadable] project continues the initial theme of the project, related to effects of superoxide on endothelial function in[unreadable] atherosclerosis and after regression, with a new emphasis on thrombotic and antithrombotic mechanisms.[unreadable] The goal of Aim 1 is to study effects of an important antioxidant enzyme, extracellular superoxide dismutase[unreadable] (ECSOD) and a common human gene variant of that enzyme. The investigators reported that the[unreadable] heparin-binding domain (HBD) of ECSOD is essential for normal functon of ECSOD. A common gene[unreadable] variant in the HBD of ECSOD, R213G, may be an extremely important risk factor for ischemic heart[unreadable] disease. The investigators have made a recombinant adenovirus that expresses ECSOD R213G and[unreadable] propose to examine vascular effects of the gene variant. Studies are proposed to test the hypothesis that[unreadable] ECSOD, but not ECSOD R213G, attenuates inflammation and protects endothelial function after bacterial[unreadable] endotoxin.[unreadable] The goal of Aim 2 is to examine effects of atherosclerosis and ECSOD on endothelial antithrombotic[unreadable] func-tion and susceptibility to thrombosis in mice. Studies are proposed to test the hypothesis that[unreadable] accelerated thrombosis in atherosclerotic mice is caused by oxidative stress and decreased bioavailability[unreadable] of endothe-lium-derived nitric oxide, with decreased activation of anticoagulant protein C. Effects of[unreadable] atherosclerosis on endothelial antithrombotic function also will be examined in a novel strain of knock-in[unreadable] mice that express human thrombomodulin and have diminished capacity to activate anticoagulant protein[unreadable] C.[unreadable] The goal of Aim 3 is to examine effects of regression of atherosclerosis on endothelial vasomotor and[unreadable] anti-thrombotic function in mice. In "Reversa" mice, hypercholesterolemia can be reversed with a genetic[unreadable] switch. After Cre induction, the gene for microsomal triglyceride transfer protein is virtually eliminated, so[unreadable] that plasma cholesterol in LDLr-/- apoB 100/100 mice is reduced to normal levels. Studies are proposed[unreadable] to test the hypothesis that regression of atherosclerosis in Reversa mice improves endothelial vasomotor[unreadable] function in aorta and coronary arteries, reduces superoxide in blood vessels and aortic valve, and[unreadable] reverses the enhanced susceptibility to thrombosis. The long-term goal of Project 3 is to clarify[unreadable] fundamental mechanisms by which superoxide and antioxidant enzymes modulate endothelial vasomotor[unreadable] and antithrombotic function.